Macrocyclic inhibitors of flaviviridae viruses

Patent metadata

Field	Value
Publication number	US-9512175-B2
Application number	US-201514821458-A
Country	US
Kind code	B2
Filing date	Aug 7, 2015
Priority date	Jun 8, 2012
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

Provided are compounds of Formula:

and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.

First claim

What is claimed is:

1. A method for treating a Flaviviridae viral infection in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein:
A is a bond, —O—, —S(O) n —, —NH—, —N((C 1 -C 4 )alkyl)- or (C 1 -C 2 )alkylene;
A 1 is —CR 9 ═CR 9 —,

wherein B is arylene, heteroarylene, cycloalkylene or heterocycloalkylene;
A 2 is —CH(R 8 )-arylene, —CH(R 8 )-heteroarylene, —CH(R 8 )-heterocycloalkylene, —CH(R 8 )— cycloalkylene, arylene, heteroarylene or cycloalkylene, wherein A 2 is optionally substituted with one or more substituents selected from the group consisting of oxo, —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —N(R 9 ) 2 , halo, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, cyano and (C 1 -C 8 )alkyl;
X 1 is a bond, —O—, —NH—, —N((C 1 -C 4 )alkyl)- or heterocycloalkylene;
R 1 and R 2 are independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, halo, cyano or (C 1 -C 4 )alkanoyl; or
R 1 and R 2 , when taken together with the carbon to which they are both attached, form —C(═O)—, —C(═S)— or —C(═N(C 1 -C 4 )alkyl)-;
R 3 is H or (C 1 -C 4 )alkyl which is optionally substituted with halo, cyano, hydroxy or (C 1 -C 4 )alkoxy;
R 4a and R 4b are independently H, (C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, heterocycloalkyl, heterocycloalkyl(C 1 -C 4 )alkyl, cycloalkyl or cycloalkyl(C 1 -C 4 )alkyl, wherein each of R 4a and R 4b is optionally substituted with one or more substituent selected from the group consisting of cyano, (C 1 -C 8 )alkoxy, —COOH, —C(O)O—(C 1 -C 8 )alkyl, halo, hydroxyl, amino, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, —C(O)-mono(C 1 -C 8 )alkylamino, —C(O)-di(C 1 -C 8 )alkylamino, —C(O)-heterocycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each substituent is optionally substituted with one or more halo, heterocycloalkyl or aryl;
R 5a and R 5b are independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, aryl, heterocycloalkyl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl or heterocycloalkyl(C 1 -C 4 )alkyl, wherein R 5a and R 5b are independently optionally substituted with one or more substituent selected from the group consisting of —N 3 , cyano, —COOH, halo, hydroxyl, amino, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, aryl and heteroaryl, or R 5a and R 5b together form a spirocycle having Formula (a):

wherein one or more carbon ring atoms of Formula (a) is optionally replaced by a nitrogen, oxygen or sulfur atom, and wherein a ring atom of Formula (a) is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, —NH 2 , —C(O)O—(C 1 -C 8 )alkyl, —C(O)-di(C 1 -C 8 )alkylamino, —C(O)—(C 1 -C 8 )alkyl, —C(O)-heterocycloalkyl, —S(O) 2 R 10 , —OSi(R 10 ) 3 , (C 1 -C 4 )alkyl, cyano(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 8 )alkanoyl and aryl(C 1 -C 4 )alkyl;
R 6a , R 6b , R 7a and R 7b are independently H, hydroxyl, cyano, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, —CH 2 CH 2 CR 9 (═N(C 1 -C 4 )alkoxy), aryl, heterocycloalkyl, cycloalkyl, —SR 9 , —S(O)R 9 , —S(O) 2 R 9 or —N(R 9 ) 2 , wherein each of R 6a , R 6b , R 7a and R 7b is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, cyano, (C 1 -C 4 )alkyl, (C 1 -C 8 )alkoxy, aryl, cycloalkyl, heterocycloalkyl, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, —NHS(O)R 9 , —NHC(O)R 9 , —OC(O)—(C 1 -C 8 )alkyl-C(O)O—(C 1 -C 8 )alkyl and (C 1 -C 8 )alkanoyl, wherein each —OC(O)—(C 1 -C 8 )alkyl or (C 1 -C 8 )alkoxy is optionally substituted with one or more amino, —OC(O)O—(C 1 -C 8 )alkyl or —Si(R 10 ) 3 ; or
R 6a and R 6b together form a spirocycle having Formula (a);
each R 8 is independently H, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl, wherein R 8 is optionally substituted with —OR, —N(R 9 ) 2 , —CON(R 9 ) 2 or cyano;
each R 9 is independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl;
each R 10 is independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, cycloalkyl(C 1 -C 4 )alkyl or aryl, wherein R 10 is optionally substituted with one or more halo;
each n is independently 0, 1 or 2; and
m is 1, 2, 3, 4 or 5.

2. The method of claim 1 , wherein A is methylene.

3. The method of claim 1 , wherein A 1 is ethenylene, propenylene, ethylene, propylene, oxypropylene, oxypropenylene, pyrazolylene, phenylene or pyrimidinylene.

4. The method of claim 1 , wherein A 1 is

5. The method of claim 1 , wherein A 2 is —CH(R 8 )-arylene or —CH(R 8 )-heteroarylene.

6. The method of claim 1 , wherein A 2 is —CH(R 8 )-quinolinylene, —CH(R 8 )-isoquinolinylene, —CH(R 8 )-naphthyridinylene, —CH(R 8 )-cinnolinylene, —CH(R 8 )-quinoxalinylene, —CH(R 8 )-phenylene or —CH(R 8 )-halophenylene.

7. The method of claim 1 , wherein A 2 is

8. The method of claim 1 , wherein X 1 is —O— or —NH—.

9. The method of claim 1 , wherein R 1 and R 2 , when taken together with the carbon to which they are both attached, form —C(═O)—.

10. The method of claim 1 , wherein R 3 is H.

11. The method of claim 1 , wherein R 6a is H and R 6b is H or (C 1 -C 4 )alkyl, or R 6a and R 6b together form a spirocycle having Formula (a).

12. The method of claim 1 , wherein R 6a and R 6b form

13. The method of claim 1 , wherein R 3 is H; R 5a is H; R 5b is H, (C 1 -C 8 )alkyl, hydroxy(C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, azido(C 1 -C 8 )alkyl, aryl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl(C 1 -C 4 )alkyl or arylheterocycloalkyl(C 1 -C 4 )alkyl; R 6a is H; and R 6b is H, (C 1 -C 4 )alkyl or hydroxy(C 1 -C 4 )alkyl.

14. The method of claim 1 , wherein X 1 is —O— or —NH—: R 1 and R 2 , when taken together with the carbon to which they are both attached, form —C(═O)—; R 3 is H; R 4a is H; R 4b is methyl; R 5a is H and R 5b is iso-propyl, propenyl or propynyl; and R 8 is methyl.

15. The method of claim 1 , which is a compound of Formula II:

or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein:
A 2 is —CH(R 8 )-arylene, —CH(R 8 )-heteroarylene, —CH(R 8 )-h

Assignees

• Gilead Sciences Inc
• Selcia Ltd

Inventors

• Aciro Caroline
• Chiva Jean Yves
• Dean David Kenneth
• Dunbar Neil Andrew
• Highton Adrian John
• Jansa Petr
• Karki Kapil Kumar
• Keats Andrew John
• Lazarides Linos
• Mackman Richard
• Pettit Simon Neil
• Poullennec Karine G
• Schrier Adam James
• Siegel Dustin Scott
• Steadman Victoria Alexandra

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/18

  for HIV · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title